New anti-obesity medications based on gut-derived nutrient-stimulated hormones (incretins) induce substantial weight loss in randomised trials, enhanced by combining actions on multiple receptors. Semaglutide (a glucagon-like peptide-1 receptor agonist, GLP-1ra), tirzepatide (GLP-1 and GIP receptor dual agonist) and retatrutide (GLP-1, GIP, and glucagon-receptor triple agonist), induce up to ~15-24% weight loss in adults with overweight and obesity, with improvement in cardiovascular risk factors. However, these agents also cause rapid and significant loss of lean mass (~6 kg, ~10%), comparable to a decade or more of ageing. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. In a two-year randomised controlled trial (RCT) of men with central adiposity and dysglycemia, testosterone treatment on a background of lifestyle intervention increased muscle mass (~0.4 kg) and reduced fat (~4.6 kg). However, in a 12-week 2x2 factorial RCT, exercise training outperformed testosterone treatment. Studies indicate that supervised resistance exercise training interventions with duration over 10 weeks can elicit increases in lean mass (~3 kg) and strength (~25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared to either alone. Retaining lean mass during incretin therapy could potentially blunt body weight (and fat) re-gain on cessation of weight loss pharmacotherapy. In overweight/obese adults with type 2 diabetes, 48-weeks treatment with bimagrumab, a monoclonal antibody targeting the myostatin signalling pathway, increased muscle mass (~1.7 kg, 3.6%), and reduced fat (~7.5 kg, 20%). Bimagrumab also has been trialled in conjunction with semaglutide and tirzepatide. Pending further results and availability of potential new therapies, tailored resistance exercise training should be recommended as an adjunct to incretin therapy, to optimise changes in body composition by preserving lean mass while achieving fat loss.